Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells

Blood Neoplasia Pub Date : 2024-10-24 DOI:10.1016/j.bneo.2024.100052

Anne P. de Groot , Chelsea R. Wilson , Ellen Weersing , Jacobine S. Pouw , Albertina Dethmers-Ausema , Huong Nguyen , Evan F. W. Chen , Alok Shaurya , Linda Smit , Fraser Hof , Gerald de Haan

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Abstract

Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The polycomb group protein chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. Because leukemic cells are highly self-renewing, we tested whether pharmacological targeting of CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7 inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.

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药理靶向 CBX7 可改变表观遗传格局并诱导白血病细胞分化

摘要白血病细胞的自我更新会导致功能障碍血细胞的积累和正常造血的抑制。多聚酶群蛋白chromobox 7（CBX7）是一种表观遗传调节因子，可抑制分化和细胞周期停滞所需的基因，从而促进自我更新。由于白血病细胞具有很强的自我更新能力，我们测试了药理学靶向 CBX7 是否会减少人类白血病细胞的自我更新并诱导其分化。我们发现，现有的和新开发的 CBX7 抑制剂会抑制表观基因组，从而减少组蛋白 2A 的泛素化，并减少 CBX7 与其靶基因的结合。这导致体外细胞生长减少、白血病细胞分化增加，以及原发性白血病细胞在异种移植模型中的移植延迟。因此，以 CBX7 为药物靶点是治疗白血病的一种新方法。

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Blood Neoplasia

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